Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease
Alcoholic liver disease (ALD) is a primary cause of morbidity and mortality in the United States and constitutes a significant socioeconomic burden. Previous work has implicated oxidative stress and endoplasmic reticulum (ER) stress in the etiology of ALD; however, the complex and interrelated natur...
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| Format: | Article |
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Wiley
2012-01-01
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| Series: | Journal of Toxicology |
| Online Access: | http://dx.doi.org/10.1155/2012/207594 |
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| author | James J. Galligan Rebecca L. Smathers Colin T. Shearn Kristofer S. Fritz Donald S. Backos Hua Jiang Christopher C. Franklin David J. Orlicky Kenneth N. MacLean Dennis R. Petersen |
| author_facet | James J. Galligan Rebecca L. Smathers Colin T. Shearn Kristofer S. Fritz Donald S. Backos Hua Jiang Christopher C. Franklin David J. Orlicky Kenneth N. MacLean Dennis R. Petersen |
| author_sort | James J. Galligan |
| collection | DOAJ |
| description | Alcoholic liver disease (ALD) is a primary cause of morbidity and mortality in the United States and constitutes a significant socioeconomic burden. Previous work has implicated oxidative stress and endoplasmic reticulum (ER) stress in the etiology of ALD; however, the complex and interrelated nature of these cellular responses presently confounds our understanding of ethanol-induced hepatopathy. In this paper, we assessed the pathological contribution of oxidative stress and ER stress in a time-course mouse model of early-stage ALD. Ethanol-treated mice exhibited significant hepatic panlobular steatosis and elevated plasma ALT values compared to isocaloric controls. Oxidative stress was observed in the ethanol-treated animals through a significant increase in hepatic TBARS and immunohistochemical staining of 4-HNE-modified proteins. Hepatic glutathione (GSH) levels were significantly decreased as a consequence of decreased CBS activity, increased GSH utilization, and increased protein glutathionylation. At the same time, immunoblot analysis of the PERK, IRE1α, ATF6, and SREBP pathways reveals no significant role for these UPR pathways in the etiology of hepatic steatosis associated with early-stage ALD. Collectively, our results indicate a primary pathogenic role for oxidative stress in the early initiating stages of ALD that precedes the involvement of the ER stress response. |
| format | Article |
| id | doaj-art-bc997f31c12d464188ce5ec19231de24 |
| institution | DOAJ |
| issn | 1687-8191 1687-8205 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Toxicology |
| spelling | doaj-art-bc997f31c12d464188ce5ec19231de242025-08-20T03:23:19ZengWileyJournal of Toxicology1687-81911687-82052012-01-01201210.1155/2012/207594207594Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver DiseaseJames J. Galligan0Rebecca L. Smathers1Colin T. Shearn2Kristofer S. Fritz3Donald S. Backos4Hua Jiang5Christopher C. Franklin6David J. Orlicky7Kenneth N. MacLean8Dennis R. Petersen9Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USAAlcoholic liver disease (ALD) is a primary cause of morbidity and mortality in the United States and constitutes a significant socioeconomic burden. Previous work has implicated oxidative stress and endoplasmic reticulum (ER) stress in the etiology of ALD; however, the complex and interrelated nature of these cellular responses presently confounds our understanding of ethanol-induced hepatopathy. In this paper, we assessed the pathological contribution of oxidative stress and ER stress in a time-course mouse model of early-stage ALD. Ethanol-treated mice exhibited significant hepatic panlobular steatosis and elevated plasma ALT values compared to isocaloric controls. Oxidative stress was observed in the ethanol-treated animals through a significant increase in hepatic TBARS and immunohistochemical staining of 4-HNE-modified proteins. Hepatic glutathione (GSH) levels were significantly decreased as a consequence of decreased CBS activity, increased GSH utilization, and increased protein glutathionylation. At the same time, immunoblot analysis of the PERK, IRE1α, ATF6, and SREBP pathways reveals no significant role for these UPR pathways in the etiology of hepatic steatosis associated with early-stage ALD. Collectively, our results indicate a primary pathogenic role for oxidative stress in the early initiating stages of ALD that precedes the involvement of the ER stress response.http://dx.doi.org/10.1155/2012/207594 |
| spellingShingle | James J. Galligan Rebecca L. Smathers Colin T. Shearn Kristofer S. Fritz Donald S. Backos Hua Jiang Christopher C. Franklin David J. Orlicky Kenneth N. MacLean Dennis R. Petersen Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease Journal of Toxicology |
| title | Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease |
| title_full | Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease |
| title_fullStr | Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease |
| title_full_unstemmed | Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease |
| title_short | Oxidative Stress and the ER Stress Response in a Murine Model for Early-Stage Alcoholic Liver Disease |
| title_sort | oxidative stress and the er stress response in a murine model for early stage alcoholic liver disease |
| url | http://dx.doi.org/10.1155/2012/207594 |
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